Department of Genetics and Genome Biology, University of Leicester, Leicester, LE1 7RH, United Kingdom.
Leicester School of Allied Health Sciences, Faculty of Health and Life Sciences, De Montfort University, Leicester, LE1 9BH, United Kingdom.
PLoS Genet. 2020 Nov 10;16(11):e1009129. doi: 10.1371/journal.pgen.1009129. eCollection 2020 Nov.
The enzyme kynurenine 3-monooxygenase (KMO) operates at a critical branch-point in the kynurenine pathway (KP), the major route of tryptophan metabolism. As the KP has been implicated in the pathogenesis of several human diseases, KMO and other enzymes that control metabolic flux through the pathway are potential therapeutic targets for these disorders. While KMO is localized to the outer mitochondrial membrane in eukaryotic organisms, no mitochondrial role for KMO has been described. In this study, KMO deficient Drosophila melanogaster were investigated for mitochondrial phenotypes in vitro and in vivo. We find that a loss of function allele or RNAi knockdown of the Drosophila KMO ortholog (cinnabar) causes a range of morphological and functional alterations to mitochondria, which are independent of changes to levels of KP metabolites. Notably, cinnabar genetically interacts with the Parkinson's disease associated genes Pink1 and parkin, as well as the mitochondrial fission gene Drp1, implicating KMO in mitochondrial dynamics and mitophagy, mechanisms which govern the maintenance of a healthy mitochondrial network. Overexpression of human KMO in mammalian cells finds that KMO plays a role in the post-translational regulation of DRP1. These findings reveal a novel mitochondrial role for KMO, independent from its enzymatic role in the kynurenine pathway.
犬尿氨酸 3-单加氧酶（KMO）在犬尿氨酸途径（KP）中起着关键分支点的作用，KP 是色氨酸代谢的主要途径。由于 KP 与几种人类疾病的发病机制有关，因此 KMO 和控制途径中代谢通量的其他酶是这些疾病的潜在治疗靶点。虽然 KMO 在真核生物中定位于线粒体外膜，但尚未描述 KMO 的线粒体作用。在这项研究中，研究了缺乏犬尿氨酸 3-单加氧酶的黑腹果蝇在体外和体内的线粒体表型。我们发现，果蝇 KMO 同源物（朱砂）的功能丧失等位基因或 RNAi 敲低会导致线粒体发生一系列形态和功能改变，这些改变与 KP 代谢物水平的变化无关。值得注意的是，朱砂与帕金森病相关基因 Pink1 和 parkin 以及线粒体分裂基因 Drp1 发生遗传相互作用，这表明 KMO 参与了线粒体动力学和线粒体自噬，这些机制控制着健康线粒体网络的维持。在哺乳动物细胞中过表达人 KMO 发现，KMO 在 DRP1 的翻译后调节中发挥作用。这些发现揭示了 KMO 的一种新的线粒体作用，与它在犬尿氨酸途径中的酶作用无关。
